Pharmaceutical formulation of fluticasone propionate

ABSTRACT

There is provided according to the invention a pharmaceutical aerosol formulation which comprises: 
     (i) fluticasone propionate and 
     (ii) a hydrofluoroalkane (HFA) propellant, characterised in that the fluticasone propionate is completely dissolved in the formulation. The invention also provided canisters containing the formulation and uses thereof.

This is a United States patent application being filed under 37 C.F.R.1.53(b) claiming priority to GB9921396.9 filed Sep. 11, 1999 in theUnited Kingdom; for which GB0014451.9 was filed Jun. 13, 2000 andGB0018654.4 was filed Jul. 28, 2000 in the United Kingdom.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a pharmaceutical formulation for use inthe administration of medicaments by inhalation. In particular, thisinvention relates to a pharmaceutical formulation of fluticasonepropionate for use in metered dose inhalers (MDI's). The invention alsorelates to methods for their preparation and to their use in therapy.

2. Description of the Background Art

Inhalers are well known devices for administering pharmaceuticallyactive materials to the respiratory tract by inhalation. Such activematerials commonly delivered by inhalation include bronchodilators suchas β2 agonists and anticholinergics, corticosteroids, anti-allergics andother materials that may be efficiently administered by inhalation, thusincreasing the therapeutic index and reducing side effects of the activematerial.

(6a, 11b, 16a, 17a)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy) androsta-1,4-diene-17-carbothioic acid, S-fluoromethyl ester was described as ananti-inflammatory steroid by U.S. Pat. No. 4,335,121. This compound isalso known by the generic name of fluticasone propionate and has sincebecome widely known as a highly effective steroid in the treatment ofinflammatory diseases, such as asthma and chronic obstructive pulmonarydisease (COPD).

Metered dose inhalers (MDI's) are the most common type of a wide rangeof inhaler types and utilise a liquefied propellant to expel dropletscontaining the pharmaceutical product to the respiratory tract as anaerosol. MDI formulations are generally characterised as solutionformulations or suspension formulations.

The most commonly used aerosol propellants for medicaments have beenFreon 11 (CCl₃F) in admixture with Freon 12 (CCl₂F₂) and Freon 114(CF₂Cl.CF₂Cl). However, these propellants are now believed to provokethe degradation of stratospheric ozone and their use is now being phasedout to eliminate the use of all CFC containing aerosol propellants.There is thus a need to provide an aerosol formulation for medicamentswhich employ so called ‘ozone-friendly’ propellants.

Hydrofluoroalkanes (HFAs; known also as hydrofluorocarbons or HFCs)contain no chlorine and are considered less destructive to ozone andthese are proposed substitutes for CFCs. In particular,1,1,1,2-tetrafluoroethane (HFA 134a) and1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to bethe best candidates for non-CFC propellants.

The efficiency of an aerosol device, such as an MDI, is a function ofthe dose deposited at the appropriate site in the lungs. Deposition isaffected by several factors, of which one of the most important is theaerodynamic particle size. Solid particles and/or droplets in an aerosolformulation can be characterised by their mass median aerodynamicdiameter (MMAD, the diameter around which the mass aerodynamic diametersare distributed equally).

Particle deposition in the lung depends largely upon three physicalmechanisms:

1. impaction, a function of particle inertia;

2. sedimentation due to gravity; and

3. diffusion resulting from Brownian motion of fine, submicrometer (<1μm) particles.

The mass of the particles determines which of the three main mechanismspredominates.

The effective aerodynamic diameter is a function of the size, shape anddensity of the particles and will affect the magnitude of forces actingon them. For example, while inertial and gravitational effects increasewith increasing particle size and particle density, the displacementsproduced by diffusion decrease. In practice, diffusion plays little partin deposition from pharmaceutical aerosols. Impaction and sedimentationcan be assessed from a measurement of the MMAD which determines thedisplacement across streamlines under the influence of inertia andgravity, respectively.

Aerosol particles of equivalent MMAD and GSD (geometric standarddeviation) have similar deposition in the lung irrespective of theircomposition. The GSD is a measure of the variability of the aerodynamicparticle diameters.

For inhalation therapy there is a preference for aerosols in which theparticles for inhalation have a diameter of about 0.5 to 5 μm. Particleswhich are larger than 5 μm in diameter are primarily deposited byinertial impaction in the orthopharynx, particles 0.5 to 5 μm indiameter, influenced mainly by gravity, are ideal for deposition in theconducting airways, and particles 0.5 to 3 μm in diameter are desirablefor aerosol delivery to the lung periphery. Particles smaller than 0.5μm may be exhaled.

Respirable particles are generally considered to be those withaerodynamic diameters less than 5 μm. These particles, particularlythose with a diameter of about 3 μm, are efficiently deposited in thelower respiratory tract by sedimentation.

It has been recently demonstrated in patients with mild and severeairflow obstruction that the particle size of choice for a β2 agonist oranticholinergic aerosol should be approximately 3 μm (Zaanen, P. et al,Int. J. Pharm. (1994) 107, 211-217, Int. J. Pharm. (1995) 114, 111-115,Thorax (1996), 51, 977-980.)

Many of the factors relevant to the MMAD of particles are relevant todroplets and the additional factors of rate of solvent evaporation, andsurface tension are also important.

In suspension formulations, particle size in principle is controlledduring manufacture by the size to which the solid medicament is reduced,usually by micronisation. However, if the suspended drug has theslightest solubility in propellant, a process known as Ostwald Ripeningcan lead to particle size growth. Also, particles may have tendency toaggregate, or adhere to parts of the MDI eg. canister or valve. Theeffect of Ostwald ripening and particularly of drug deposition may beparticularly severe for potent drugs (including fluticasone propionate)which need to be formulated in low doses. Solution formulations do notsuffer from these disadvantages, but suffer from different ones in thatparticle or droplet size is both a function of rate of evaporation ofthe propellant from the formulation, and of the time between release offormulation from canister and the moment of inhalation. Thus, it may besubject to considerable variability and is generally hard to control.

Besides its impact on the therapeutic profile of a drug, the size ofaerosol particles has an important impact on the side effect profile ofa drug. For example, it is well known that the orthopharynx depositionof aerosol formulations of steroids can result in side effects such ascandidiasis of mouth and throat. Accordingly, throat deposition of suchaerosol formulations is generally to be avoided. Furthermore, a highersystemic exposure to the aerosol particles due to deep lung penetrationcan enhance the undesired systemic effects of certain drugs. Forexample, the systemic exposure to certain steroids can produce sideeffects on bone metabolism and growth.

SUMMARY OF THE INVENTION

Thus, according to the present invention we provide a pharmaceuticalaerosol formulation for use in a metered dose inhaler, comprising (i)fluticasone propionate and (ii) a hydrofluoroalkane (HFA) propellant;and characterised in that the fluticasone propionate is completelydissolved in the formulation.

DETAILED DESCRIPTION OF THE INVENTION

The formulation according to the invention will generally contain asolubilisation agent to aid solubilisation of the fluticasone propionatein the formulation. Suitable solubilisation agents include propyleneglycol and ethanol, preferably ethanol. Other suitable solubilisationagents include ethers (eg dimethyl ether). Alkanes may also be of use. Afurther solubilisation agent of interest is dimethoxymethane (methylal)which has good solvency properties. We have also found ethylacetate tobe a solubilising agent with good solvency properties.

As a particular aspect of the present invention we provide apharmaceutical aerosol formulation comprising (i) fluticasonepropionate, (ii) a hydrofluoroalkane (HFA) propellant, (iii) a lowvolatility component to increase the mass median aerodynamic diameter(MMAD) of the aerosol particles on actuation of the inhaler and (iv) asolubilisation agent in sufficient quantity to solubilise thefluticasone propionate in the formulation.

The presence of the low volatility component in the solution formulationincreases the fine particle mass (FPM) as defined by the content ofstages 3-5 of an Andersen Cascade Impactor on actuation of theformulation relative to solutions formulations which omit thiscomponent. Solution formulations which omit the higher volatilitycomponent generally give rise to a particle size distribution which havea higher content of finer particles; such distributions generally do notmatch the distribution of the existing commercialised suspensionformulations which contain CFC's and may therefore not bebio-equivalent.

Examples of HFA propellants include 1,1,1,2-tetrafluoroethane (HFA134a)and 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) and mixtures thereo'.The preferred propellant is 1,1,1,2-tetrafluoroethane (HFA134a). Analternative propellant of interest is1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227).

The preferred low volatility component is glycerol, propylene glycol orpolyethyleneglycol (eg PEG 200 or PEG 400), especially glycerol.Polyethylene glycol is also of particular interest, especially PEG400.Preferably it is present in an amount of 0.5 to 3% (w/w), especiallyaround 1% (w/w).

The preferred solubilisation agent is ethanol.

More specifically, the present invention can be defined as apharmaceutical aerosol formulation which comprises:

(i) fluticasone propionate;

(ii) 1,1,1,2-tetrafluoroethane (HFA 134a);

(iii) 0.5-3% (w/w) glycerol; and

(iv) a solubilisation agent (particularly ethanol) in sufficientquantity to solubilise the fluticasone propionate in the formulation.

We prefer the formulation to be suitable for delivering a therapeuticamount of fluticasone propionate in one or two actuations. Preferably,the formulation will be suitable for delivering 25-250 μg per actuation,especially 25 μg, 50 μg, 125 μg or 250 μg per actuation. However, asmentioned in the foregoing, the amount of ethanol required to dissolvehigh concentrations of fluticasone propionate may tend to depress thevapour pressure of the propellant to an undesirable degree. The vapourpressure should desirably remain above around 50 psi. Therefore theformulation is most suitable for delivering 25-125 μg per actuation,especially 25-50 μg per actuation.

The formulation according to the invention will be used in associationwith a suitable metering valve. We prefer that the formulation isactuated by a metering valve capable of delivering a volume of between50 μl and 100 μl, eg 50 μl or 63 μl. 100 μl is also suitable. When a 50μl metering volume is used, the final concentration of fluticasonepropionate delivered per actuation would be 0.1% w/v (which equates to0.1 g of fluticasone propionate per 100 ml of formulation) or approx.0.083% w/w (which equates to 0.083 g of fluticasone propionate per 100 gof formulation) for a 50 μg dose, 0.25% (w/v) or approx. 0.21% (w/w) fora 125 μg dose, 0.5% (w/v) or approx. 0.42% (w/w) for a 250 μg dose and0.05% (w/v) or approx 0.042% (w/w) for a 25 μg dose. Wherein a 63 μlmetering volume is used, the final concentration of fluticasonepropionate delivered per actuation would be 0.079% (w/v) or approx.0.067% (w/w) for a 50 μg dose, 0.198% (w/v) or approx. 0.167% (w/w) fora 125 μg dose, 0.397% (w/v) or approx. 0.333% (w/w) for a 250 μg doseand 0.04% (w/v) or approx. 0.033% (w/w) for a 25 μg dose. When a 100 μlmetering volume is used, the final concentration of fluticasonepropionate delivered per actuation would be 0.05% w/v (which equates to0.05 g of fluticasone propionate per 100 ml of formulation) or approx.0.042% w/w (which equates to 0.042 g of fluticasone propionate per 100 gof formulation) for a 50 g dose, 0.125% (w/v) or approx. 0.11% (w/w) fora 125 μg dose, 0.25% (w/v) or approx. 0.21% (w/w) for a 250 μg dose and0.025% (w/v) or approx 0.021% (w/w) for a 25 μg dose. The previouslyquoted w/w figures are approximate in that they do not compensate in themismatch in density between HFA134a and ethanol, however the precisefigures may be readily determined.

The formulation is most suitable for concentrations of fluticasonepropionate in the range 0.025 to 0.25% (w/v), preferably 0.025 to 0.15%(w/v), more preferably 0.035 to 0.15% (w/v), particularly 0.04 to 0.1%(w/v). A concentration of 0.025 to 0.04% (w/v) is also of particularinterest. Formulations of the present invention containing such lowconcentrations of fluticasone propionate may have particular physicalstability advantages relative to suspension formulations containing thesame wherein particles of fluticasone propionate may be susceptible toOstwald ripening or to drug deposition on the canister wall or on partsof the valve as discussed above. Drug deposition is especiallyproblematic in low strength fluticasone propionate suspensionformulations because the amount of drug lost through deposition oninternal surfaces of the metered dose inhaler can represent asignificant proportion of the total available drug and therefore have asignificant effect on dosing uniformity through the life of the product.The solution formulations of the present invention overcome orsubstantially mitigate such disadvantages.

Use of a larger metering chamber eg 100 μl will generally be preferred.

We prefer the formulation to contain between 0.5 and 2% w/w, morepreferably between 0.8 and 1.6% w/w, particularly between 1.0 and 1.6%w/w glycerol. Another range of particular interest is 0.5-1% (w/w)glycerol. We especially prefer to use 1.3% (w/w) glycerol. We alsoespecially prefer to use 1.0% w/w glycerol.

Depending on the final concentration of fluticasone propionate in theformulation, the propellant, and the precise amount of low volatilitycomponent, the concentration of solubilisation agent (eg ethanol)required will vary. So as not to suppress the vapour pressure of thepropellant to an undesirable extent, the amount of ethanol shouldpreferably not exceed around 35%. The amount of ethanol will morepreferably be in the range 5 to 30%, particularly 5 to 20%, moreparticularly 10 to 20%. A range of 7 to 16% wow is also particularlypreferred, more particularly 7 to 11% w/w.

When the concentration of fluticasone propionate is around 0.1% w/v andthe propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of16-24% w/w eg 16-18% w/w, especially around 16% w/w is particularlysuitable but is more preferably 20-22% w/w especially around 21% w/w.When the concentration of fluticasone propionate is around 0.05% w/v andthe propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of7-11% w/w eg 7-8% w/w, especially around 7% w/w is particularly suitablebut is more preferably 9-11% w/w especially around 10% w/w. When theconcentration of fluticasone propionate is around 0.079% w/v and thepropellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 15-17%w/w especially around 16% is suitable. When the concentration offluticasone propionate is around 0.198% w/v and the propellant is1,1,1,2-tetrafluoroethane, an amount of ethanol of 34-36% w/w eg around35% is suitable. When the concentration of fluticasone propionate isaround 0.025% w/v and the propellant is 1,1,1,2-tetrafluoroethane, anamount of ethanol of 7-9% w/w especially around 8%, more preferablyaround 7% is suitable.

When the concentration of fluticasone propionate is around 0.0250% w/vand the propellant is 1,1,1,2,3,3,3-heptafluoro-n-propane, an amount ofethanol of 13-15% w/w especially around 14% is suitable. When theconcentration of fluticasone propionate is around 0.05% w/v and thepropellant is 1,1,1,2,3,3,3-heptafluoro-n-propane, an amount of ethanolof 17-19% w/w especially around 18% is suitable. When the concentrationof fluticasone propionate is around 0.05% w/v and the propellant is1,1,1,2-tetrafluoroethane, an amount of ethylacetate as solubilisationagent of 13-16% w/w especially around 15% is suitable. When theconcentration offluticasone propionate is around 0.05% w/v and thepropellant is 1,1,1,2-tetrafluoroethane, an amount of dimethoxymethane(methylal) as solubilisation agent of 13-16% w/w especially around 15%is suitable.

The above generally described formulations are particularly preferred inconjunction with 1.0-1.6% w/w glycerol, particularly 1.0% w/w glycerolor 1.3% w/w glycerol.

Formulations according to the invention which are free of surfactantsare preferred. Formulations according to the invention which are free ofall excipients besides the solubilisation agent (eg ethanol), lowvolatility component (such as glycerol) and the propellant areparticularly preferred.

Formulations according to the invention will preferably containfluticasone propionate as the only medicament. However formulationswhich contain medicaments in addition to fluticasone propionate such asbeta adrenergic agonists and anti-cholinergic compounds may also becontemplated.

The pharmaceutical composition according to the present invention may befilled into canisters suitable for delivering pharmaceutical aerosolformulations. Canisters generally comprise a container capable ofwithstanding the vapour pressure of the HFA propellant, such as plasticor plastic-coated glass bottle or preferably a metal can, for example analuminium can which may optionally be anodised, lacquer-coated and/orplastic-coated, which container is closed with a metering valve. It maybe preferred that canisters be coated with a fluorocarbon polymer asdescribed in WO 96/32151, for example, a co-polymer of polyethersulphone(PES) and polytetrafluoroethylene (PTFE). Another polymer for coatingthat may be contemplated is FEP (fluorinated ethylene propylene). Themetering valves are designed to deliver a metered amount of theformulation per actuation and incorporate a gasket to prevent leakage ofpropellant through the valve. The gasket may comprise any suitableelastomeric material such as for example low density polyethylene,chlorobutyl, black and white butadiene-acrylonitrile rubbers, butylrubber and neoprene. Thermoplastic elastomer valves as described inWO92/11190 and valves containing EPDM rubber as described in WO95/02651are especially suitable. Suitable valves are commercially available frommanufacturers well known in the aerosol industry, for example, fromValois, France (eg. DF10, DF30, DF60), Bespak pic, UK (eg. BK300, BK356,BK357) and 3M-Neotechnic Ltd, UK (eg. Spraymiser™). The DF31 valve ofValois, France is also suitable.

Valve seals, especially the gasket seal, and also the seals around themetering chamber, will preferably be manufactured of a material which isinert to and resists extraction into the contents of the formulation,especially when the contents include ethanol.

Valve materials, especially the material of manufacture of the meteringchamber, will preferably be manufactured of a material which is inert toand resists distortion by contents. of the formulation, especially whenthe contents include ethanol. Particularly suitable materials for use inmanufacture of the metering chamber include polyesters egpolybutyleneterephthalate (PBT) and acetals, especially PBT.

Materials of manufacture of the metering chamber and/or the valve stemmay desirably be fluorinated, partially fluorinated or impregnated withfluorine containing substances in order to resist drug deposition.

Valves which are entirely or substantially composed of metal components(eg Spraymiser, 3M-Neotechnic) are especially preferred for useaccording to the invention.

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method a metering valve is crimped onto an aluminium canto form an empty canister. The medicament is added to a charge vesseland a mixture of ethanol, low volatility component and liquefiedpropellant is pressure filled through the charge vessel into amanufacturing vessel. An aliquot of the formulation is then filledthrough the metering valve into the canister. Typically, in batchesprepared for pharmaceutical use, each filled canister is check-weighed,coded with a batch number and packed into a tray for storage beforerelease testing.

In an alternative process, an aliquot of the liquified formulation isadded to an open canister under conditions which are sufficiently coldthat the formulation does not vaporise, and then a metering valvecrimped onto the canister.

In an alternative process an aliquot of medicament dissolved in thesolubilising agent and any low-volatility component is dispensed into anempty canister, a metering valve is crimped on, and then the propellantis filled into the canister through the valve.

Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing.

Each filled canister is conveniently fitted into a suitable channellingdevice prior to use to form a metered dose inhaler for administration ofthe medicament into the lungs or nasal cavity of a patient. Suitablechannelling devices comprise, for example a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient eg. a mouthpiece actuator.

In a typical arrangement the valve stem is seated in a nozzle blockwhich has an orifice leading to an expansion chamber. The expansionchamber has an exit orifice which extends into the mouthpiece. Actuator(exit) orifice diameters in the range 0.15-0.45 mm particularly 0.2-0.45mm are generally suitable eg 0.15, 0.22, 0.25, 0.30, 0.33 or 0.42 mm. Wehave found that it is advantageous to use a small diameter eg 0.25 mm orless, particularly 0.22 mm since this tends to result in a higher FPMand lower throat deposition. 0.15 mm is also particularly suitable. Thedimensions of the orifice should not be so small that blockage of thejet occurs.

Actuator jet lengths are typically in the range 0.30-1.7 mm eg 0.30,0.65 or 1.50 mm. Smaller dimensions are preferred eg 0.65 mm or 0.30 mm.

Metered dose inhalers are designed to deliver a fixed unit dosage ofmedicament per actuation or ‘puff’, for example in the range of 25 to250 μg medicament per puff.

Administration of medicament may be indicated for the treatment of mild,moderate or severe acute or chronic symptoms or for prophylactictreatment. Treatment may be of asthma, chronic obstructive pulmonarydisease (COPD) or other respiratory disorder. It will be appreciatedthat the precise dose administered will depend upon the age andcondition of the patient, the quantity and frequency of administrationwill ultimately be at the discretion of the attendant physician.Typically, administration may be one or more times, for example from 1to 8 times per day, giving for example 1,2,3 or 4 puffs each time. Thepreferred treatment regime is 1 or 2 puffs of 25, 50, 125 or 250 μg/pufffluticasone propionate, 2 times per day.

The filled canisters and metered dose inhalers described herein comprisefurther aspects of the present invention.

A still further aspect of the present invention comprises a method oftreating respiratory disorders such as, for example, asthma or chronicobstructive pulmonary disease (COPD), which comprises administration byinhalation of an effective amount of a formulation herein beforedescribed.

A further aspect of the present invention comprises the use of aformulation herein before described in the manufacture of a medicamentfor the treatment of respiratory disorders, eg. asthma or chronicobstructive pulmonary disease (COPD).

As mentioned above the advantages of the invention include the fact thatformulations according to the invention may be more environmentallyfriendly, more stable, less susceptible to Oswald ripening or drugdeposition onto internal surfaces of a metered dose inhaler, have betterdosing uniformity, deliver a higher FPM, give lower throat deposition,be more easily or economically manufactured, or may be otherwisebeneficial relative to known formulations.

The invention is illustrated with reference to the following examples:

EXAMPLES 1 AND 2

Formulations may be prepared with compositions as follows:

Fluticasone propionate: 0.1% w/v 0.05% w/v Ethanol: 16% w/w 7% Glycerol:1.3% w/w 1.3% 1, 1, 1, 2-tetrafluoroethane: to 100% to 100%

These solution formulations may be filled into an aluminium canisterunder pressure and fitted with a metering valve having a 50 μl meteringchamber. These formulations are suitable for delivering 50 μg or 25 μgfluticasone propionate per actuation respectively.

EXAMPLE 3

Formulations were prepared with compositions as follows:

Form. 3a Form. 3b Form. 3c Fluticasone propionate: 0.1% w/v 0.079% w/v0.05% w/v Ethanol: 21% w/w 16% w/w 10% Glycerol: 1.0% w/w 1.0% w/w 1.0%1, 1, 1, 2-tetrafluoroethane: to 100% to 100% to 100%

These solution formulations were filled into aluminium canisters (120actuations/canister; overage of 40 actuations) under pressure and fittedwith a metering valve (Valois DF60) having metering chambers of volume50 μl, 63 μl and 100 μl respectively.

These formulations are suitable for delivering 50 μg fluticasonepropionate per actuation.

EXAMPLE 4

Formulations were prepared with compositions as follows:

Form. 4a Form. 4b Form. 4c Fluticasone propionate: 0.1% w/v 0.079% w/v0.05% w/v Ethanol: 21% w/w 16% w/w 10% 1, 1, 1, 2-tetrafluoroethane: to100% to 100% to 100%

These solution formulations were filled into aluminium canisters (120actuations/canister; overage of 40 actuations) under pressure and fittedwith a metering valve (Valois DF60) having metering chambers of volume50 μl, 63 μl and 100 μl respectively.

These formulations are suitable for delivering 50 μg fluticasonepropionate per actuation.

EXAMPLE 5

A formulation was prepared with compositions as follows:

Fluticasone propionate: 0.198% w/v

Ethanol: 35% w/w

Glycerol: 1.0% w/w

1,1,1,2-tetrafluoroethane: to 100%

This solution formulation was filled into an aluminium canisters (120actuations/canister; overage of 40 actuations) under pressure and fittedwith a metering valve (Valois DF60) having metering chamber of volume 63μl.

This formulation is suitable for delivering 125 μg fluticasonepropionate per actuation.

EXAMPLE 6

A formulation was prepared with compositions as follows:

Fluticasone propionate: 0.198% w/v

Ethanol: 35% w/w

1,1,1,2-tetrafluoroethane: to 100%

This solution formulation was filled into an aluminium canisters (120actuations/canister; overage of 40 actuations) under pressure and fittedwith a metering valve (Valois DF60) having metering chamber of volume 631 μl. This formulation is suitable for delivering 125 μg fluticasonepropionate per actuation.

EXAMPLE 7

Formulations were prepared with compositions as follows:

Form. 7a Form. 7b Form. 7c Fluticasone propionate: 0.05% w/v 0.05% w/v0.05% w/v Ethanol: 10% w/w 10% w/w 10% w/w Glycerol: 0.5% w/w 2% w/w 3%w/w 1, 1, 1, 2-tetrafluoroethane: to 100% to 100% to 100%

These solution formulations were filled into aluminium canisters (120actuations/canister; overage of 40 actuations) under pressure and fittedwith a metering valve (Valois DF60) having metering chamber of volume100 μl. These formulations are suitable for delivering 50 μg fluticasonepropionate per actuation.

EXAMPLE 8

Formulations were prepared with compositions as follows:

Fluticasone propionate: 0.025% w/v 0.025% w/v Ethanol: 8% w/w 7% w/wGlycerol: 1.0% w/w 1.0% w/w 1, 1, 1, 2-tetrafluoroethane: to 100% to100%

These solution formulations were filled into an aluminium canisters (120actuations/canister; overage of 40 actuations) under pressure and fittedwith a metering valve (Valois DF60) having metering chamber of volume100 μl.

These formulations are suitable for delivering 25 μg fluticasonepropionate per actuation.

EXAMPLE 9

Formulations were prepared with compositions as follows:

Formulation 9a:

Fluticasone propionate: 0.05% w/v

Dimethoxymethane: 15% w/w

1,1,1,2-tetrafluoroethane: to 100%

Formulation 9b:

Fluticasone propionate: 0.05% w/v

Ethylacetate: 15% w/w

1,1,1,2-tetrafluoroethane: to 100%

Formulation 9c:

Fluticasone propionate: 0.05% w/v

Dimethoxymethane: 15% w/w

Glycerol: 1% w/w

1,1,1,2-Letrafluoroethane: to 100%

Formulation 9d:

Fluticasone propionate: 0.05% w/v

Ethylacetate: 15% w/w

Glycerol: 1% w/w

1,1,1,2-tetrafluoroethane: to 100%

These solution formulations were filled into aluminium canisters (120actuations/canister; overage of 40 actuations) under pressure and fittedwith a metering valve (Valois DF60) having metering chamber of volume100 μl. These formulations are suitable for delivering 50 μg fluticasonepropionate per actuation.

EXAMPLE 10

Formulations were prepared with compositions as follows:

Formulation 10a:

Fluticasone propionate: 0.05% w/v

Ethanol: 10% w/w

Glycerol: 1%w/w

1,1,1,2-tetrafluoroethane: to 100%

Formulation 10b:

Fluticasone propionate: 0.05% w/v

Ethanol: 10% w/w

PEG 200: 1% w/w

1,1,1,2-tetrafluoroethane: to 100%

Formulation 10c:

Fluticasone propionate: 0.05% w/v

Ethanol: 10% w/w

PEG 400: 1%w/w

1,1,1,2-tetrafluoroethane: to 100%

Formulation 10d:

Fluticasone propionate: 0.05% w/v

Ethanol: 10% w/w

Propylene glycol: 1% w/w

1,1,1,2-tetrafluoroethane: to 100%

Formulation 10e:

Fluticasone propionate: 0.05% w/v

Ethanol: 18% w/w

1,1,1,2,3,3,3-heptafluoro-n-propane: to 100%

Formulation 10f:

Fluticasone propionate: 0.05% w/v

Ethanol: 18% w/w

Glycerol: 1% w/w

1,1,1,2,3,3,3-heptafluoro-n-propane: to 100%

Formulation 10g:

Fluticasone propionate: 0.025% w/v

Ethanol: 14% w/w

1,1,1,2,3,3,3-heptafluoro-n-propane: to 100%

Formulation 10h:

Fluticasone propionate: 0.025% w/v

Ethanol: 14% w/w

Glycerol: 1% w/w

1,1,1,2,3,3,3-heptafluoro-n-propane: to 100%

Formulation 10i:

Fluticasone propionate: 0.025% w/v

Ethanol: 7% w/w

1,1,1,2-tetrafluoroethane: to 100%

Formulation 10j:

Fluticasone propionate: 0.025% w/v

Ethanol: 7% w/w

Glycerol: 1% w/w

1,1,1,2-tetrafluoroethane: to 100%

These solution formulations were filled into aluminium canisters (120actuations/canister; overage of 40 actuations) under pressure and fittedwith a metering valve (Valois DF60) having metering chamber of volume 63μl. These formulations are suitable for delivering 31.5 μg (10a-10e) or15.75 μg (10f,10g) fluticasone propionate per actuation. However theperformance of these formulations is a model for formulations that woulddeliver 50 μg and 25 μg fluticasone propionate using a metering valve of100 μl.

Andersen Cascade Impaction Data

Formulations as described in Examples 3, 4, 5 and 6 were profiled usingan Andersen Cascade Impactor, using a 0.22 mm (orifice)×0.65 mm O(etlength) actuator from Bespak (BK621 variant). Testing was performed oncanisters at “beginning of use” (BoU) and delivered drug from 10actuations was collected in the instrument after 4 priming actuationswere fired to waste. Results are shown in Tables 1-4 and FIGS. 1-4 and11. For comparison, data from a Flixotide Evohaler (trademark)(particulate fluticasone propionate suspensed in HFA134a (excipientfree) 50 μg per actuation) product is also shown in some figures.

The 0.079% w/v fluticasone propionate products of Examples 3 and 4 (50μg per actuation; 63 μl metering chamber) were profiled using anAndersen Cascade Impactor in a study to see the effect of actuatororifice diameter and length.

Three actuators were used:

0.50 mm diameter orifice×1.50 mm jet length

0.33 mm diameter orifice×1.50 mm jet length

0.22 mm diameter orifice×0.65 mm jet length

Results are shown in Table 5 and FIGS. 5 to 9. For comparison, data froma Flixotide Evohaler (trademark) (particulate fluticasone propionatesuspensed in HFA134a (excipient free) 50 μg per actuation) product isalso shown in some figures.

The results show the best performance (as indicated by highest FPM) inproducts containing a relatively low concentration of ethanol (sayaround 10%) and containing glycerol (say around 1%). A small actuatororifice diameter (say around 0.22 mm) is also seen to be preferred.

The solubility of fluticasone propionate in ethanol in the presence ofHFA134a is shown in FIG. 10.

A study was performed on the 0.05% w/v fluticasone propionateformulations (HFA134a/10% ethanol) of Examples 3 (Formulation 3c),4(Formulation 4c) and 7 (Formulations 7a, 7b and 7c) with a 0.22 mm×0.65mm actuator using an Andersen Cascade Impactor to consider the effect ofglycerol content on the following properties: (i). MMAD, (ii) throatdeposition, and (iii) stage 3-7 deposition. The results are shown inFIGS. 12-14 . For maximum deposition in the desired region withoutexcessive throat deposition the optimal glycerol concentration appearsto be around 0.8-1.6% w/w, particularly 1.0-1.6% w/w.

A study was performed using an Andersen Cascade Impactor to compare theproperties of formulations containing different solubilising agents. Anactuator of dimensions 0.22 mm×0.65 mm was used for the study. Theresults of the analysis of the formulations of Example 9 Formulations9a, 9b, 9c and 9d and a comparison with the formulations of Example 3Formulation 3c and Example 4 Formulation 4c are shown in Table 6 andFIG. 15. The ethanol with glycerol profile clearly appears the mostattractive since it demonstrates the highest FPM content in view of thehigh dosing in stages 4 and 4 relative to the other profiles.Nevertheless the methylal profiles also looked of significant interestin view of the very low throat deposition. The addition of 1% glycerolshifted the methylal profile to lower stages only to a small extent,perhaps in view of its greater volatility than ethanol. A higherpercentage of glycerol would be expected to increase the magnitude ofthe shift.

A study was performed using an Andersen Cascade Impactor to compare theproperties of formulations containing different low volatilitycomponents. An actuator of dimensions 0.22 mm×0.65 mm was used for thestudy. The results of the analysis of the formulations of Example 10Formulations 10a to 10d are shown in Table 7 and FIG. 16. Particularlygood profiles are shown by glycerol and PEG400 which demonstraterelatively low throat deposition and high dosing in stages 4 and 5.

A study was performed using an Andersen Cascade Impactor to study theproperties of 0.05% fluticasone propionate formulations containing1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) as propellant. An actuatorof dimensions 0.22 mm×0.65 mm was used for the study. The results of theanalysis of the formulations of Example 10 Formulations 10e and 10f areshown in Table 8 and FIG. 17. Comparison with the HFA134a aerosolformulation of Formulation 10a is shown.

A study was performed using an Andersen Cascade Impactor to study theproperties of 0.025% fluticasone propionate formulations containing1,1,1,2-tetrafluoroethane (HFA134a) or1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) as propellant. An actuatorof dimensions 0.22 mm×0.65 mm was used for the study. The results of theanalysis of the formulations of Example 10 Formulations log to 10j areshown in Table 9 and FIGS. 18 and 19. The HFA134a product with ethanolshows a particularly attractive profile eg as shown by a high totaldelivered dose and a relatively low throat deposition.

BRIEF DESCRIPTION OF THE DRAWINGS

Table 1: Effect of valve on FPM in fluticasone propionate HFA134asolution aerosols (50 μg/actuation)

Table 2: Effect of different levels of ethanol on FPM in fluticasonepropionate/HFA134a solution aerosols

Table 3: Effect of different levels of ethanol on FPM in fluticasonepropionate/HFA134a solution aerosols (valve size effect ignored)

Table 4: Cascade impaction analysis of fluticasone propionate/HFA134asolution aerosols (125 μg/actuation) containing 35% ethanol or 35%ethanol and 1% glycerol

Table 5: Cascade impaction analysis of fluticasone propionate/HFA134asolution aerosols (50 μg/actuation) containing 16% ethanol or 16%ethanol and 1% glycerol

Table 6: Cascade impaction analysis of fluticasone propionate/HFA134asolution aerosols (50 μg/actuation) containing various solubiling agentswith and without 1% glycerol

Table 7: Cascade impaction analysis of fluticasone propionate/HFA134asolution aeroscis (50 μg /actuation) containing various low volatilitycomponents

Table 8: Cascade impaction analysis of fluticasone propionate solutionaerosols (50 μg/actuation) containing various propellants

Table 9: Cascade impaction analysis of fluticasone propionate solutionaerosols (25 μg/actuation) containing various propellants

FIG. 1: Effect of valve size and glycerol on FPM in fluticasonepropionate solution aerosols in HFA134a (50 μg/actuation)

FIG. 2: Effect of level of ethanol on FPM in various fluticasonepropionate/HFA134a solution aerosols with no addition of glycerol

FIG. 3: Effect of level of ethanol on FPM in various fluticasonepropionate/HFA134a solution aerosols with addition of 1% glycerol

FIG. 4: Effect of glycerol on FPM in fluticasone propionate 125μg/HFA134a solution aerosols containing 35% ethanol or 35% ethanol and1% glycerol

FIG. 5: Effect of actuator dimensions on FPM and throat in fluticasonepropionate/HFA134a solution aerosols (50 μg/actuation) containing 16%ethanol

FIG. 6: Effect of actuator dimensions on FPM and throat in fluticasonepropionate/HFA134a solution aerosols (50 μg/actuation) containing 16%ethanol and 1% ethanol

FIG. 7: The effect of addition of glycerol on FPM in fluticasonepropionate 50 g/HFA134a solution aerosols containing 16% ethanol or 16%ethanol and 1% glycerol (0.22 mm diameter actuator orifice)

FIG. 8: The effect of addition of glycerol on FPM in fluticasonepropionate 50 μg/HFA134a solution aerosols containing 16% ethanol or 16%ethanol and 1% glycerol (0.33 mm diameter actuator orifice)

FIG. 9: Effects of addition of glycerol and actuator dimensions on FPMin fluticasone propionate 50μg/HFA134a solution aerosols containing 16%ethanol or 16% ethanol and 1% glycerol (all actuator variants)

FIG. 10: Solubility of fluticasone propionate in ethanol/HFA134a

FIG. 11: Effects of addition of glycerol and actuator dimensions on FPMin fluticasone propionate 50 μg/HFA134a solution aerosols containing 10%ethanol or 10% ethanol and 1% glycerol

FIG. 12: Effects of addition of glycerol on MMAD in fluticasonepropionate 50 μg/HFA134a solution aerosols containing 10% ethanol

FIG. 13: Effects of addition of glycerol on throat deposition influticasone propionate 50μg/HFA134a solution aerosols containing 10%ethanol

FIG. 14: Effects of addition of glycerol on stage 3-7 deposition influticasone propionate 50 μg/HFA134a solution aerosols containing 10%ethanol

FIG. 15: Cascade impaction analysis of fluticasone propionate/HFA134asolution aerosols (50 μg/actuation) containing ethanol, methylal orethylacetate as solubilising agent, with and without 1% glycerol

FIG. 16: Cascade impaction analysis of fluticasone propionate/HFA134asolution aerosols (50 μg/actuation) containing various low volatilitycomponents and 10% ethanol

FIG. 17: Cascade impaction analysis of fluticasone propionate/HFA227solution aerosols (50 μg actuation) containing 18% ethanol with andwithout 1% glycerol and comparison with HFA134a aerosol

FIG. 18: Cascade impaction analysis of fluticasone propionate in HFA227or HFA134a solution aerosols (25 μg actuation) containing ethanol

FIG. 19: Cascade impaction analysis of fluticasone propionate in HFA227or HFA134a solution aerosols (25 μg actuation) containing ethanol and 1%glycerol

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

Above mentioned patents and patent applications are hereinbeforeincorporated by reference.

Abbreviations FPM fine particle mass FP fluticasone propionate m/cmetering chamber BoU beginning of use PEG polyethyleneglycol Form.Formulation MMAD mass median aerodynamic diameter

TABLE 1 The effect of valve on FPM in FP50 μg solution aerosols All datagenerated with 0.22 mm actuator, except HFA134a suspension producttested with 0.50 mm actuator μg Resuts Cascade Impaction FormulationEthanol only Ethanol and 1% glycerol HFA134a* Ethanol conc. 10% w/w 16%w/w 21% w/w 10% w/w 16% w/w 21% w/w — Valve size 100 μl 63 μl 50 μl 100μl 63 μl 50 μl 50 μl Product FP FP FP FP FP FP FP Product strength 50 μg50 μg 50 μg 50 μg 50 μg 50 μg 50 μg Device 5.7 4.3 5.3 5.2 4.1 5.2 6.6Throat 12.7  15.2  21.2  16.0  17.1  23.1 13.5  Stage 0 4.5 2.2 2.8 3.43.1 2.9 1.6 Stage 1 0.3 0.3 0.3 0.7 0.5 0.6 0.8 Stage 2 0.2 0.2 0.2 1.10.9 0.8 1.1 Stage 3 0.3 0.2 0.3 5.4 3.9 3.8 3.2 Stage 4 0.9 0.6 1.0 7.65.9 5.2 9.8 Stage 5 9.8 6.5 7.0 8.5 7.3 5.3 11.2  Stage 6 8.6 6.8 5.62.4 1.6 1.6 1.4 Stage 7 5.5 3.4 2.8 1.4 1.0 0.8 0.3 Filter 4.7 2.7 2.10.9 0.7 0.5 0.2 Total 53.2  42.4  48.6  52.6  46.1  49.8  48.0  Totalex-device 47.5  38.1  43.3  47.4  42.0  44.6  43.3  FPM, St3 + St4 + St511.0  7.3 8.3 21.5  17.1  14.3  15.7  FPM, St5 + St6 + St7 23.9  16.7 15.4  12.3  9.9 7.7 8.8 *Flixotide Evohaler suspension formulation

TABLE 2 Effect of different levels of Ethanol on FPM in FP/HFA134asolution aerosols All fitted with 63 μl m/c and tested with 0.22 mmactuator % Results Cascade Impaction Formulation Ethanol only Ethanoland 1% glycerol Ethanol conc. 16% w/w 35% w/w 16% w/w 35% w/w Valve size63 μl 63 μl 63 μl 63 μl Product FP FP FP FP Product strength 50 μg 125μg 50 μg 125 μg Device 10.1 12.1 8.6 12.6 Throat 35.8 62.6 38.8 63.1Stage 0 5.2 6.5 6.3 5.8 Stage 1 0.7 0.0 1.0 1.0 Stage 2 0.5 0.0 1.7 1.0Stage 3 0.5 0.9 8.2 2.9 Stage 4 1.4 1.9 12.6 4.9 Stage 5 15.3 6.5 15.94.9 Stage 6 16.0 4.7 3.3 1.9 Stage 7 8.0 1.9 2.1 1.0 Filter 6.4 2.8 1.41.0 Total 100.0 100.0 100.0 100.0 Total ex-device 89.9 87.9 91.4 87.4FPM St3 + St4 + St5 17.2 9.3 36.7 12.6 FPM, St5 + St6 + St7 39.3 13.121.3 7.8

TABLE 3 Effect of different levels of Ethanol on FPM in FP/HFA134asolution aerosols (valve size effect ignored) All tested with 0.22 mmactuator, except HFA134a suspension product tested with 0.50 mm actuator% Results Cascade Impaction Formulation Ethanol only Ethanol and 1%glycerol HFA134a* Ethanol conc. 10% w/w 16% w/w 21% w/w 35% w/w 10% w/w16% w/w 21% w/w 35% w/w — Valve size 100 μl 63 μl 50 μl 63 μl 100 μl 63μl 50 μl 63 μl 50 μl Product FP FP FP FP FP FP FP FP FP Product strength50 μg 50 μg 50 μg 125 μg 50 μg 50 μg 50 μg 125 μg 50 μg Device 10.7 10.110.9 12.1 9.9 8.6 10.4 12.6 13.3 Throat 23.9 35.8 43.6 62.6 30.4 38.846.4 63.1 27.2 Stage 0 8.5 5.2 5.8 6.5 6.5 6.3 5.8 5.8 3.2 Stage 1 0.60.7 0.6 0.0 1.3 1.0 1.2 1.0 1.6 Stage 2 0.4 0.5 0.4 0.0 2.1 1.7 1.6 1.02.2 Stage 3 0.6 0.5 0.6 0.9 10.3 8.2 7.6 2.9 6.4 Stage 4 1.7 1.4 2.1 1.914.4 12.6 10.4 4.9 19.7 Stage 5 18.4 15.3 14.4 6.5 16.2 15.9 10.6 4.922.5 Stage 6 16.2 16.0 11.5 4.7 4.6 3.3 3.2 1.9 2.8 Stage 7 10.3 8.0 5.81.9 2.7 2.1 1.6 1.0 0.6 Filter 8.8 6.4 4.3 2.8 1.7 1.4 1 1.0 0.4 Total100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100 Total ex-device 89.389.8 89.1 87.8 90.1 91.3 89.6 87.4 86.7 FPM, St3 + St4 + St5 20.7 17.217.1 9.3 40.9 36.7 28.6 12.7 48.7 FPM, St5 + St6 + St7 44.9 39.3 31.713.1 23.5 21.3 15.4 7.8 25.9 *Flixotide Evohaler Suspension Formulation

TABLE 4 Cascade Impaction analysis of FP/HFA134a 125 μg solutionaerosols containing 35% ethanol or 35% ethanol and 1% glycerol (0.22 mmactuator 63 μl m/c Valois valve) Formulation Ethanol only Ethanol andglycerol Stage of Use BoU (act. 1-10) BoU (act. 1-10) Sample IDFP125/A3/1 FP125/A3/1 Mean FP125/A3/1 FP125/A3/2 Mean Device 13.6 10.712.2 14.4 10.9 12.7 Throat 59.2 73.9 66.6 64.7 64.4 64.6 Stage 0 6.8 6.96.9 5.6 5.9 5.8 Stage 1 0.5 0.3 0.4 0.5 0.5 0.5 Stage 2 0.3 0.1 0.2 0.60.8 0.7 Stage 3 0.5 0.4 0.5 2.4 2.6 2.5 Stage 4 2.2 1.7 2.0 4.8 5.0 4.9Stage 5 8.5 6.1 7.3 5.5 5.0 5.3 Stage 6 5.2 4.1 4.7 2.0 1.7 1.9 Stage 72.4 1.8 2.1 1.1 0.8 1.0 Filter 2.1 2.7 2.4 0.7 0.5 0.6 Total 101.3 108.7105.0 102.3 98.1 100.2 Tota ex-device 87.7 98.0 92.9 87.9 87.2 87.6 FPM,St3 + St4 + St5 11.2 8.2 9.7 12.7 12.6 12.7 FPM, St5 + St6 + St7 16.112.0 14.1 8.6 7.5 8.1 All means, Totals and FPMs were calculated byExcel on rounded individual data A3 = Actuator 0.22 mm × 0.65 mm

TABLE 5 Cascade Impaction analysis of FP/HFA134a 50 μg solution aerosolscontaining 16% ethanol or 16% ethanol and 1% glycerol (63 μl m/c Valoisvalve DF60 MK37) Formulation Ethanol only Stage of Use BoU (act. 1-10)Product FP50 FP50 FP50 FP50 FP50 FP50 Actuator 0.50 mm 0.50 mm Mean 0.33mm 0.33 mm Mean 0.22 mm 0.22 mm Mean Device 4.2 4.2 4.2 5.3 4.2 4.8 5.23.3 4.3 Throat 32.4 32.3 32.4 25.1 25.9 25.5 13.9 16.4 15.2 Stage 0 1.41.4 1.4 1.0 1.7 1.4 2.3 2.1 2.2 Stage 1 0.1 0.1 0.1 0.1 0.1 0.1 0.3 0.30.3 Stage 2 0.0 0.1 0.1 0.1 0.1 0.1 0.2 0.2 0.2 Stage 3 0.1 0.1 0.1 0.10.3 0.2 0.2 0.2 0.2 Stage 4 0.3 0.3 0.3 0.3 0.5 0.4 0.7 0.5 0.6 Stage S1.8 2.0 1.9 3.6 3.9 3.8 6.4 6.5 6.5 Stage 6 1.5 1.6 1.6 3.5 3.5 3.5 6.86.8 6.8 Stage 7 0.9 1.0 1.0 2.1 2.0 2.1 3.4 3.4 3.4 Filter 1.3 1.4 1.42.1 2.6 2.4 2.7 2.7 2.7 Total 44.0 44.5 44.3 43.3 44.8 44.1 42.1 42.442.3 Total ex-device 39.0 39.0 39.0 37.0 40.0 38.5 36.0 38.0 37.0 FPM,St3 + St4 + St5 2.0 2.0 2.0 4.0 4.0 4.0 7.0 7.0 7.0 FPM, St5 + St6 + St74.2 4.6 4.4 9.2 9.4 9.3 16.6 16.7 16.7 Ethanol and glycerol FP/134a 50μg BoU (act. 1-10) Initial, BoU FP50 FP50 FP50 FP50 Mean 0.33 mm 0.33 mmMean 0.22 mm 0.22 mm Mean 0.50 mm Device 4.7 4.4 4.6 4.4 3.7 4.1 6.6Throat 26.2 28.5 27.4 16.3 17.8 17.1 13.5 Stage 0 1.0 1.3 1.2 3.6 2.63.1 1.6 Stage 1 0.2 0.4 0.3 0.6 0.4 0.5 0.8 Stage 2 0.3 0.4 0.4 1.0 0.70.9 1.1 Stage 3 1.4 1.5 1.5 4.3 3.5 3.9 3.2 Stage 4 2.6 2.5 2.6 6.2 5.55.9 9.8 Stage 5 4.0 3.5 3.8 7.5 7.0 7.3 11.2 Stage 6 1.0 0.9 1.0 1.8 1.41.6 1.4 Stage 7 0.6 0.5 0.6 1.0 0.9 1.0 0.3 Filter 0.5 0.4 0.5 0.7 0.60.7 0.2 Total 42.5 44.3 43.4 47.4 44.1 45.8 44.9 Total ex-device 38.039.0 38.5 44.0 43.0 43.5 43.3 FPM, St3 + St4 + St5 8.0 8.0 8.0 18.0 17.017.5 17.3 FPM, St5 + St6 + St7 5.6 4.9 5.3 10.3 9.3 9.8 9.6 All means,Totals and FPMs were calculated by Excel on rounded individual data*Flixotide Evohaler suspension formulation

TABLE 6 Cascade Impaction analysis of FP/HFA134a 50 μg solution aerosolscontaining various solubilising agents (100 μl Valois valve, Bespak0.22mm x 0.65mm actuator) Formulation FP 50ug FP 50pg FP 50 μg Stage ofUse BoU (act. 1-10) BOU (act. 1-10) BoU (act. 1-10) Valve 100 μl 100 μl100 μl 100 μl 100 μl 100 μl LVC — 1% glycerol — 1% glycerol — 1%glycerol Solvent 15% methylal* 15% methylal 15% ethyl acetate 15% ethylacetate 10% ethanol 10% ethanol Device 5.9 6.2 9.0 6.4 4.3 4.4 Throat5.8 6.3 5.3 13.8 15.2 14.0 Stage 0 1.4 3.9 1.2 1.6 2.2 3.3 Stage 1 0.50.8 0.5 0.6 0.3 0.7 Stage 2 0.6 0.7 0.5 0.8 0.2 1.0 Stage 3 0.9 1.4 1.11.7 0.2 5.3 Stage 4 1.6 2.3 0.8 1.8 0.6 8.1 Stage 5 6.9 10.3 1.9 9.2 6.58.8 Stage 6 8.8 7.6 5.0 6.2 6.8 2.4 Stage 7 6.0 3.8 4.4 3.2 3.4 1.3Filter 4.8 2.0 3.0 2.0 2.7 0.7 Total 43.2 45.1 32.4 47.1 42.3 49.8 Totalex-device 37.3 39.0 23.4 40.7 37.0 45.5 FPM, St3 + St4 + St5 9.4 13.93.7 12.7 7.0 22.2 *Result based on one can only (can 2 data rejected asan atypical result) LVC = low volatility component

TABLE 7 Cascade Impaction analysis of FP/HFA134a 50 μg solution aerosolscontaining various low volatility components (63 μl m/c Valois valveDF60 or 100 μl Valois valve, Bespak 0.22 mm × 0.65 mm actuator)Formulation FP50 μg HFA134a Stage of Use BoU (act. 1-10) FP50 μg HFA134aFP50 μg HFAI34a FP50 μg HFAI34a Valve Normalised BoU (act. 1-10) BoU(act. 1-10) BoU (act. 1-10) 63 μl for 100 μl Normalised NormalisedNormalised LVC 1% propylene 1% propylene 63 μl for 100 μl 63 μl for 100μl 63 μl for 100 μl glycol glycol 1% PEG200 1% PEG200 1% PEG400 1%PEG400 1% glycerol 1% glycerol Solvent 10% ethanol 10% ethanol 10%ethanol 10% ethanol 10% ethanol 10% ethanol 10% ethanol 10% ethanolDevice 2.2 3.5 2.3 3.7 2.0 3.1 1.7 2.7 Throat 7.3 11.6 6.1 9.7 5.5 8.75.5 8.7 Stage 0 0.7 1.1 0.8 1.3 0.9 1.4 1.2 1.9 Stage 1 0.3 0.5 0.3 0.50.2 0.4 0.3 0.5 Stage 2 0.6 1.0 0.6 1.0 0.6 1.0 0.7 1.1 Stage 3 3.1 4.93.5 5.6 2.9 4.6 3.0 4.8 Stage 4 3.6 5.7 4.7 7.5 5.2 8.3 5.5 8.7 Stage 53.7 5.9 5.7 9.0 6.4 10.2 5.2 8.3 Stage 6 1.0 1.6 1.7 2.7 1.7 2.7 1.5 2.4Stage 7 1.4 2.2 0.9 1.4 1.0 1.5 0.7 1.1 Filter 0.6 1.0 0.1 0.2 0.6 0.90.4 0.8 Total 24.3 38.6 26.5 42.1 27.0 42.8 25.4 40.3 Total ex-device22.1 35.1 24.2 38.4 25.0 39.7 23.8 37.8 FPM, St3 + St4 + St5 10.3 16.313.8 21.9 14.5 23.0 13.6 21.6 LVC = low volatility component

TABLE 8 Cascade Impaction analysis of FP 50 μg solution aerosolscontaining various propellants (64 μl m/c Valois valve DF60 or 100 μlValois valve, Bespak 0.22 mm × 0.65 mm actuator) Formulation FP50 μgHFA227ea FP50 μg HFA227ea FP50 μg HFA134a Stage of Use BoU (act. 1-10)BoU (act. 1-10) BoU (act. 1-10) Valve Normalised Normalised Normalised63 μl for 100 μl 63 μl for 100 μl 63 μl for 100 μl LVC — — 1% glycerol1% glycerol 1% glycerol 1% glycerol Solvent 18% ethanol 18% ethanol 18%ethanol 18% ethanol 10% ethanol 10% ethanol Device 2.4 3.8 2.4 3.8 1.72.7 Throat 14.4 22.9 13.8 21.8 5.5 8.7 Stage 0 2.0 3.2 2.3 3.7 1.2 1.9Stage 1 0.3 0.5 0.4 0.6 0.3 0.5 Stage 2 0.2 0.3 0.7 1.1 0.7 1.1 Stage 30.2 0.3 2.4 3.7 3.0 4.8 Stage 4 0.4 0.6 2.9 4.6 5.5 8.7 Stage 5 3.0 4.82.4 3.8 5.2 8.3 Stage 6 2.7 4.3 0.6 1.0 1.5 2.4 Stage 7 1.4 2.2 0.3 0.50.7 1.1 Filter 1.2 1.9 0.1 0.2 0.4 0.6 Total 28.1 44.6 28.2 44.8 25.440.3 Total ex-device 25.7 40.8 25.8 41.0 23.8 37.8 FPM, St3 + St4 + St53.6 5.7 7.7 12.1 13.6 21.6 LVC = low volatility component

TABLE 9 Cascade Impaction analysis of FP 25 μg solution aerosolscontaining various propellants (63 μl m/c Valois valve DF60 or 100 μlValois valve, Bespak 0.22 mm × 0.65 mm actuator) Formulation FP25 μgHFA134a FP25 μg HFA134a FP25 μg HFA134a FP25 μg HFA134a Stage of Use BoU(act. 1-10) BoU (act. 1-10) BoU (act. 1-10) BoU (act. 1-10) ValveNormalised Normalised Normalised Normalised 63 μl for 100 μl 63 μl for100 μl 63 μl for 100 μl 63 μl for 100 μl LVC — — 1% glycerol 1% glycerol— — 1% glycerol 1% glycerol Solvent 7% ethanol 7% ethanol 7% ethanol 7%ethanol 14% ethanol 14% ethanol 14% ethanol 14% ethanol Device 1.3 2.11.1 1.7 1.1 1.7 1.0 1.6 Throat 1.3 2.1 1.6 2.5 4.2 6.7 4.5 7.1 Stage 00.1 0.2 0.3 0.5 1.1 1.7 1.5 2.4 Stage 1 0.0 0.0 0.1 0.2 0.1 0.2 0.3 0.5Stage 2 0.0 0.0 0.2 0.3 0.1 0.2 0.4 0.6 Stage 3 0.0 0.0 1.1 1.7 0.1 0.21.6 2.5 Stage 4 0.1 0.2 2.7 4.3 0.1 0.2 1.9 3.0 Stage 5 1.0 1.6 4.1 6.51.9 3.0 1.5 2.4 Stage 6 2.8 4.4 1.3 2.1 2.4 3.8 0.4 0.6 Stage 7 2.4 3.80.6 1.0 1.4 2.2 0.2 0.3 Filter 1.9 3.0 0.3 0.5 1.0 1.6 0.2 0.3 Total10.8 17.1 13.3 21.1 13.3 21.1 13.3 21.1 Total ex-device 9.5 15.1 12.219.4 2.3 19.5 12.3 19.5 FPM. St3 + St4 + 1.1 1.7 7.8 12.4 2.1 3.3 4.97.8 St5 LVC = low volatility component

What is claimed is:
 1. A pharmaceutical solution aerosol formulation which comprises: (i) fluticasone propionate at a concentration of 0.025 to 0.15% w/v (ii) a hydrofluoroalkane (HFA) propellant which is 1,1,1,2-tetrafluoroethane (HFA134a); (iii) a low volatility component at a concentration of 0.5 to 3% w/w to increase the mass median aerodynamic diameter (MMAD) of aerosol particles on actuation of an inhaler containing said formulation; and (iv) ethanol as a solubilisation agent in sufficient quantity to solubilise the fluticasone propionate in the formulation and being present at a concentration of 5 to 30% w/w; characterised in that the fluticasone propionate is completely dissolved in the formulation.
 2. A pharmaceutical formulation according to claim 1 further containing a low volatility component which is glycerol, propylene glycol or polyethylene glycol.
 3. A pharmaceutical formulation according to claim 2 containing a low volatility component which is polyethylene glycol.
 4. A pharmaceutical formulation according to claim 2 containing a low volatility component which is glycerol.
 5. A pharmaceutical formulation according to claim 1 which contains 0.5 to 3% w/w glycerol.
 6. A pharmaceutical formulation according to claim 1 which contains between 0.8 and 1.6% (w/w) glycerol as low volatility component.
 7. A pharmaceutical formulation according to claim 6 which contains between 1.0 and 1.6% (w/w) glycerol.
 8. A pharmaceutical formulation according to claim 7 which contains 1.3% (w/w) glycerol.
 9. A pharmaceutical formulation according to claim 7 which contains 1.0% (w/w) glycerol.
 10. A formulation according to claim 1 wherein the concentration of fluticasone propionate is 0.035 to 0.15% w/v.
 11. A formulation according to claim 10 wherein the concentration of fluticasone propionate is 0.04 to 0.1% w/v.
 12. A formulation according to claim 1 wherein the concentration of fluticasone propionate is 0.025 to 0.04% w/v.
 13. A formulation according to claim 1 wherein the concentration of ethanol is 10 to 20% w/w.
 14. A formulation according to claim 1 wherein the concentration of ethanol is 7 to 16% w/w.
 15. A formulation according to claim 1 wherein the concentration of ethanol is 7 to 11% w/w.
 16. A formulation according to claim 1 wherein the concentration of ethanol is 7 to 8% w/w.
 17. A formulation according to claim 1 wherein the concentration of solubilisation agent is 14 to 16% w/w.
 18. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of pharmaceutical aerosol formulation according to claim
 1. 